This disclosure is directed to a new and improved method of making 2,4-diamino-5-phenyl-6-alkyl pyrimidines and new intermediates useful in the preparation thereof.
Reference may be had to U.S. Pat. No. 2,576,939 as well as British Journal of Pharmacology and Chemotheraphy, June, 1951, Vol. 6, No. 2, p. 185 for the article entitled 2, 4-Diamino Pyrimidines - A New Series of AntiMalarials by E. A. Palco et al., for a discussion and disclosure of antimalarial compounds of the type which may be synthesized by the methods disclosed herein.
In particular, this invention is directed to a new and improved method for making antimalarial compounds of formula I ##SPC2##
where X is a halogen atom (chlorine, iodine, fluorine, or bromine) or a nitro group, Y is a halogen group (chlorine, iodine, fluorine, or bromine) or hydrogen and R is hydrogen or alkyl containing 1 to 10 carbon atoms and more preferably lower alkyl containing 1 to 4 carbon atoms (methyl, ethyl, propyl, or butyl) and more preferably for making the antimalarial compounds of formula IA ##SPC3##
where X is halogen (chlorine, iodine, fluorine, or bromine) or nitro and R is hydrogen or lower alkyl containing 1 to 4 carbon atoms (methyl, ethyl, propyl or butyl).
The compounds of formula I or IA are useful as antimalarial agents and may be administered orally in a conventional manner, e.g., tablets to humans (adults or children) at a dosage of 25 mg. weekly and at a dosage of 12.5 mg. weekly for children.
Of the compounds of formula I or IA, the compound 2,4-diamino-5-p-chlorophenyl-6-ethyl pyrimidine (pyrimethamine) has proved most successful in treating malaria infections in man and has been widely used for this purpose.
In the past, the compounds of formula I or IA have been primarily prepared by the methods disclosed in U.S. Pat. Nos. 2,602,794 and 2,576,939. Although the process of U.S. Pat. No. 2,602,794 have proven to be quite useful in practice, particularly in small scale operations, it has been difficult to date to maintain high yields in making the required intermediates as the process disclosed therein is scaled up for large scale manufacturing operations.
Unexpectedly, it has now been found that with the process of the present invention it is possible to scale up manufacture without experiencing large reductions in yield of the new intermediates compared with the yields obtainable under laboratory conditions.
Accordingly, this invention provides a new and improved process for preparing the compounds of formula I or IA much more economically than heretofore possible. The above has been accomplished by providing new and improved methods for preparing new and unobvious intermediates which are then further reacted with guanidine base to provide the compounds of formula I or IA.